Novel Restorative Therapy for Spinal Cord Injury Spinal cord injury (SCI) is a devastating traumatic CNS disorder that significantly disables about 253,000 Americans where two-thirds of the new victims are under the age of 30. Functional deficits following SCI result from damage to axons or severance cutting of axons, loss of neurons and glia, and demyelination. SCI pathology is determined not only by the initial mechanical insult, but also by secondary processes including ischemia, free-radical formation, inflammation, and excitotoxicity. Currently, there is no cure for SCI, and methylprednisolone is the only choice in the clinic, and it lacks FDA approval. Clearly, novel therapies are urgently needed to maximally reduce the disastrous outcome and more effectively improve neurological functions following SCI. Cognosci has developed the COG series of anti-inflammatory/neuroprotective peptides, which are derived from the receptor-binding region of apolipoprotein E (apoE). Our Phase I study established proof-of-principle that our parent peptide, COG133, significantly promoted functional recovery and decreased histopathological lesion size in a mouse model of compressive injury of human SCI. We exceeded our aims by finding that COG compounds are both neuroprotective and neurorestorative and appear to be promoting remyelination. Our intensive studies revealed that apoE-based COG peptides exert significant bioactivities relevant to eliminate the secondary damage and foster the recovery of SCI in the following possible pathways: (1) anti-inflammation;(2) anti-excitotoxicity and reducing intracellular Ca2+ overload;(3) reducing the production of free radical species and nitric oxide;(4) promoting the reconstruction of myelin and protecting oligodendrocytes. This Phase II proposal will capitalize on the success of our previous work to identify the drug lead for acute SCI by comparison of therapeutic efficacy of three more potent and more drug-like COG compounds in two established models of SCI. Furthermore, we will start the limited preclinical safety and toxicity studies with the identified lead compound in this grant and are planning to complete the entire safety and toxicity profiling in a future Phase II continuation grant, which is required by the FDA for an IND application before proceeding to the human clinical trials. PUBLIC HEALTH RELEVANCE: The completion of this Phase II study will enable us to select one lead candidate for the treatment of acute SCI and to proceed to FDA-required safety/toxicity profiling. To fill the critically unmet need for SCI therapy, COG compounds may represent a new generation of restorative SCI therapeutics with the dual potentials of diminishing neurodegeneration of secondary damage and rebuilding damaged axon and myelin. Considering the debilitating nature of SCI, size of the patient population, and the startling healthcare costs, the current project to develop a novel therapy for SCI has significant personal, social, and economic benefit to SCI victims and their families.